The role of the central nervous system in the initiation and maintenance of elevated blood pressure associated with hypertensive disease has been emphasized with the development of two antihypertensive drugs, clonidine and Alpha-methyldopa. Both Agents appear to act on central Alpha-adrenergic receptors mediating a decrease in systemic blood pressure. While brain adrenergic neurones appear to play a sympathoinhibitory role in cardiovascular regulation, the antihypertensive actions of clonidine and Alpha-methyldopa occur independently of this neuronal system. Preliminary studies, however, have demonstrated that clonidine inhibits the activity of central cholinergic neurones which have a sympathoexcitatory role in blood pressure regulation. The present study will employ both pharmacological and neurochemical techniques to examine the role of central cholinergic neurones in mediating the antihypertensive action of clonidine and Alpha-methyldopa. Also, the possible participation of brain acetylcholine in the development of hypertension will be examined in the spontaneously hypertensive and renal hypertensive rat. This will be accomplished by continuously recording blood pressure, heart rate and motor activity in freely-moving hypertensive rats placed on antihypertensive theraphy with clonidine or Alpha-methyldopa. The cardiovascular and behavioral effects of acute and chronic administration of these drugs will be measured in parallel with changes in regional brain cholinergic activity. The rate of brain acetylcholine synthesis will be estimated by measuring the rate of accumulation of radiolabled acetylcholine following central injection of labled precursor, choline. In another series of experiments, the function of central cholinergic neurones will be altered pharmacologically in hypertensive animals through central administration of cholinergic agonists or antagonists. The effects of altered brain cholinergic activity on the antihypertensive properties of clonidine and Alpha-methyldopa then will be examined. In the final series of experiments it will be determined as to whether the development of hypertension in these two animal models are related to changes in the regional metabolism of brain acetylcholine. This study will aid in understanding the nature of central adrenergic-cholinergic interactions involved in cardiovascular regulation, and in the underlying disfunction of this central control mechanism which may be associated with hypertensive disease.